Abstract
Simple SummaryDiffuse midline gliomas (DMGs) remain one of the most devastating childhood brain tumour types, for which there is currently no known cure. In this review we provide a summary of the existing knowledge of the molecular mechanisms underlying the pathogenesis of this disease, highlighting current analyses and novel treatment propositions. Together, the accumulation of these data will aid in the understanding and development of more effective therapeutic options for the treatment of DMGs.Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.
Highlights
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive central nervous system (CNS) pediatric tumours located in the brainstem, thalamus, spinal cord and cerebellum [1,2]
TN-C has been targeted with antibodies; this approach has shown some promise in subcutaneous glioma models, its efficacy has not been demonstrated in orthotopic DMG models, especially when the blood–brain barrier (BBB) remains intact [317]
Over the past decade we have gained valuable insights into DMG biology and recognise the role that histone and other genetic modifications play in the pathogenesis of the disease
Summary
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive central nervous system (CNS) pediatric tumours located in the brainstem, thalamus, spinal cord and cerebellum [1,2]. In 2021 the WHO further classified the inclusion of a subset of DMGs that lack the H3K27M mutation but exhibit a global loss of tri-methylation [2], potentially mediated by the overexpression of EZH inhibitory protein (EZHIP) which functionally acts as a K27M-like inhibitor of polycomb repressive complex 2 (PRC2) [11]. These tumors have been termed “diffuse midline glioma, H3 K27-altered”.
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